OsAAP6 functions as an important regulator of grain protein content and nutritional quality in rice.
Grains from cereals contribute an important source of protein to human food, and grain protein content (GPC) is an important determinant of nutritional quality in cereals. Here we show that the quantitative trait locus (QTL) qPC1 in rice controls GPC by regulating the synthesis and accumulation of glutelins, prolamins, globulins, albumins and starch. qPC1 encodes a putative amino acid transporter OsAAP6, which functions as a positive regulator of GPC in rice, such that higher expression of OsAAP6 is correlated with higher GPC. OsAAP6 greatly enhances root absorption of a range of amino acids and has effects on the distribution of various amino acids. Two common variations in the potential cis-regulatory elements of the OsAAP6 5'-untranslated region seem to be associated with GPC diversity mainly in indica cultivars. Our results represent the first step toward unravelling the mechanism of regulation underlying natural variation of GPC in rice.


Comparing the Statistical Fate of Paralogous and Orthologous Sequences.
For several decades, sequence alignment has been a widely used tool in bioinformatics. For instance, finding homologous sequences with a known function in large databases is used to get insight into the function of nonannotated genomic regions. Very efficient tools like BLAST have been developed to identify and rank possible homologous sequences. To estimate the significance of the homology, the ranking of alignment scores takes a background model for random sequences into account. Using this model we can estimate the probability to find two exactly matching subsequences by chance in two unrelated sequences. For two homologous sequences, the corresponding probability is much higher, which allows us to identify them. Here we focus on the distribution of lengths of exact sequence matches between protein-coding regions of pairs of evolutionarily distant genomes. We show that this distribution exhibits a power-law tail with an exponent [Formula: see text] Developing a simple model of sequence evolution by substitutions and segmental duplications, we show analytically and computationally that paralogous and orthologous gene pairs contribute differently to this distribution. Our model explains the differences observed in the comparison of coding and noncoding parts of genomes, thus providing a better understanding of statistical properties of genomic sequences and their evolution.


The clinical diagnosis of root caries: issues for the clinician and the researcher.
This paper, after presenting a brief case for the relevance of root caries to today's practitioner, describes the differing diagnostic needs of clinical practitioners and clinical researchers. The goal is to inform the clinician of the state-of-the-art that exists today for the diagnosis of root caries in both clinical and research settings. Differing definitions for the diagnosis of root caries are presented that are useful, respectively, for the clinician and for the clinical researcher. Reasons for why there are differing definitions for clinicians and researchers are presented. Finally, eight critical issues are presented that will have to be resolved if clinical research on root caries is to improve its rigor: (1) active vs. inactive lesions, (2) supra- vs. sub-gingival lesions, (3) lesions crossing the CEJ, (4) prior clinical treatment: a visibility issue, (5) oral debris: a visibility issue, (6) instruments for tactile clues, (7) radiographs, and (8) diagnostic conventions.


Genetic factors in type 2 diabetes: the end of the beginning?
The intensive search for genetic variants that predispose to type 2 diabetes was launched with optimism, but progress has been slower than was hoped. Even so, major advances have been made in the understanding of monogenic forms of the disease which together represent a substantial health burden, and a few common gene variants that influence susceptibility have now been unequivocally identified. Armed with a better understanding of the tools needed to detect such genes, it seems inevitable that the rate of progress will increase and the relevance of genetic information to the diagnosis, treatment, and prevention of diabetes will become increasingly tangible.


Predicting drug side-effect profiles: a chemical fragment-based approach.
Drug side-effects, or adverse drug reactions, have become a major public health concern. It is one of the main causes of failure in the process of drug development, and of drug withdrawal once they have reached the market. Therefore, in silico prediction of potential side-effects early in the drug discovery process, before reaching the clinical stages, is of great interest to improve this long and expensive process and to provide new efficient and safe therapies for patients. In the present work, we propose a new method to predict potential side-effects of drug candidate molecules based on their chemical structures, applicable on large molecular databanks. A unique feature of the proposed method is its ability to extract correlated sets of chemical substructures (or chemical fragments) and side-effects. This is made possible using sparse canonical correlation analysis (SCCA). In the results, we show the usefulness of the proposed method by predicting 1385 side-effects in the SIDER database from the chemical structures of 888 approved drugs. These predictions are performed with simultaneous extraction of correlated ensembles formed by a set of chemical substructures shared by drugs that are likely to have a set of side-effects. We also conduct a comprehensive side-effect prediction for many uncharacterized drug molecules stored in DrugBank, and were able to confirm interesting predictions using independent source of information. The proposed method is expected to be useful in various stages of the drug development process.


Animal use in pharmacology education and research: the changing scenario.
The use of animals in research and education dates back to the period when humans started to look for ways to prevent and cure ailments. Most of present day's drug discoveries were possible because of the use of animals in research. The dilemma to continue animal experiments in education and research continues with varied and confusing guidelines. However, the animal use and their handling vary in each laboratory and educational institution. It has been reported that the animals are being subjected to painful procedures in education and training unnecessarily. The extensive use of animals in toxicity studies and testing dermatological preparations has raised concerns about the ways animals are sacrificed for these "irrelevant experiments". On the other side of the coin are scientists who advocate the relevant and judicious use of animals in research so that new discoveries can continue. In this review, we discuss the evolution of the use of animals in education and research and how these have been affected in recent times owing to concerns from animal lovers and government regulations. A number of computer simulation and other models have been recommended for use as alternatives to use of animals for pharmacology education. In this review we also discuss some of these alternatives.


BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts.
The BTB-Kelch protein Krp1 is highly and specifically expressed in skeletal muscle, where it is proposed to have a role in myofibril formation. We observed significant upregulation of Krp1 in C2 cells early in myoblast differentiation, well before myofibrillogenesis. Krp1 has a role in cytoskeletal organization and cell motility; since myoblast migration and elongation/alignment are important events in early myogenesis, we hypothesized that Krp1 is involved with earlier regulation of differentiation. Krp1 protein levels were detectable by 24 h after induction of differentiation in C2 cells and were significantly upregulated by 48 h, i.e., following the onset myogenin expression and preceding myosin heavy chain (MHC) upregulation. Upregulation of Krp1 required a myogenic stimulus as signaling derived from increased myoblast cell density was insufficient to activate Krp1 expression. Examination of putative Krp1 proximal promoter regions revealed consensus E box elements associated with myogenic basic helix-loop-helix binding. The activity of a luciferase promoter-reporter construct encompassing this 2,000-bp region increased in differentiating C2 myoblasts and in C2 cells transfected with myogenin and/or MyoD. Knockdown of Krp1 via short hairpin RNA resulted in increased C2 cell number and proliferation rate as assessed by bromodeoxyuridine incorporation, whereas overexpression of Krp1-myc had the opposite effect; apoptosis was unchanged. No effects of changed Krp1 protein levels on cell migration were observed, either by scratch wound assay or live cell imaging. Paradoxically, both knockdown and overexpression of Krp1 inhibited myoblast differentiation assessed by expression of myogenin, MEF2C, MHC, and cell fusion.


The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics of Noninvasive Diagnosis (END) Multicenter Study Group.
The study aim was to determine observational differences in costs of care by the coronary disease diagnostic test modality. A number of diagnostic strategies are available with few data to compare the cost implications of the initial test choice. We prospectively enrolled 11,372 consecutive stable angina patients who were referred for stress myocardial perfusion tomography or cardiac catheterization. Stress imaging patients were matched by their pretest clinical risk of coronary disease to a series of patients referred to cardiac catheterization. Composite 3-year costs of care were compared for two patients management strategies: 1) direct cardiac catheterization (aggressive) and 2) initial stress myocardial perfusion tomography and selective catheterization of high risk patients (conservative). Analysis of variance techniques were used to compare costs, adjusting for treatment propensity and pretest risk. Observational comparisons of aggressive as compared with conservative testing strategies reveal that costs of care were higher for direct cardiac catheterization in all clinical risk subsets (range: $2,878 to $4,579), as compared with stress myocardial perfusion imaging plus selective catheterization (range: $2,387 to $3,010, p < 0.0001). Coronary revascularization rates were higher for low, intermediate and high risk direct catheterization patients as compared with the initial stress perfusion imaging cohort (13% to 50%, p < 0.0001); cardiac death or myocardial infarction rates were similar (p > 0.20). Observational assessments reveal that stable chest pain patients who undergo a more aggressive diagnostic strategy have higher diagnostic costs and greater rates of intervention and follow-up costs. Cost differences may reflect a diminished necessity for resource consumption for patients with normal test results.


Treatment of left anterior descending artery aneurysm.
Coronary artery aneurysms (CAAs) are rare and their management is controversial. Their incidence varies from 1,5% to 5% of the coronary angiographies, with predilection of the right coronary artery. Unruptured coronary aneurysms are often silent and may remain undiagnosed. The etiology can be either congenital or acquired. We describe a case of a left anterior descending artery (LAD) aneurysm treated with an off-pump surgical revascularization with a LIMA to LAD without exclusion or ligature of the aneurysm.


Further investigation of simian immunodeficiency virus Vif function in human cells.
Primate lentivirus Vif proteins function by suppressing the antiviral activity of the cell-encoded apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) proteins APOBEC3G and APOBEC3F. It has been hypothesized that species-specific susceptibilities of APOBEC proteins to Vif proteins may help govern the transmission of primate lentiviruses to new host species. Consistent with this view and with previous results, we report that the Vif proteins of several diverse simian immunodeficiency viruses (SIVs) that are not known to infect humans are not effective inhibitors of human APOBEC3G or APOBEC3F when assessed in transient-transfection experiments. Unexpectedly, this lack of SIV Vif function did not prevent the replication of two vif-deficient SIVs (SIVtan and SIVmnd1; isolated from tantalus monkeys and mandrills, respectively) in a human T-cell line, HUT78, that expresses both APOBEC 3G and APOBEC3F, a finding which demonstrates that some SIVs are partially resistant to the antiretroviral effects of these enzymes irrespective of Vif function. Additional virus replication studies also revealed that the Vif protein of SIVtan is, in fact, active in human T cells, as it substantially enhanced the replication of its cognate virus and human immunodeficiency virus type 1. In sum, we now consider it improbable that species-specific restrictions to SIV Vif function can explain the lack of human infection with certain SIVs. Instead, our data reveal that the species-specific modulation of Vif function is more complex than previously envisioned and that additional (as-yet-unidentified) viral or host factors may be involved in regulating this dynamic interaction between host and pathogen.


Pain catastrophizing as a risk factor for chronic pain after total knee arthroplasty: a systematic review.
Total knee arthroplasty (TKA) is a common and costly surgical procedure. Despite high success rates, many TKA patients develop chronic pain in the months and years following surgery, constituting a public health burden. Pain catastrophizing is a construct that reflects anxious preoccupation with pain, inability to inhibit pain-related fears, amplification of the significance of pain vis-à-vis health implications, and a sense of helplessness regarding pain. Recent research suggests that it may be an important risk factor for untoward TKA outcomes. To clarify this impact, we systematically reviewed the literature to date on pain catastrophizing as a prospective predictor of chronic pain following TKA. We searched MEDLINE, EMBASE, and PsycINFO databases to identify articles related to pain catastrophizing, TKA, risk models, and chronic pain. We reviewed titles and abstracts to identify original research articles that met our specified inclusion criteria. Included articles were then rated for methodological quality. including methodological quality. Due to heterogeneity in follow-up, analyses, and outcomes reported across studies, a quantitative meta-analysis could not be performed. We identified six prospective longitudinal studies with small-to-mid-sized samples that met the inclusion criteria. Despite considerable variability in reported pain outcomes, pain catastrophizing was identified as a significant predictor of chronic pain persisting ≥3 months following TKA in five of the studies assessed. Limitations of studies included lack of large-scale data, absence of standardized pain measurements, inadequate multivariate adjustment, such as failure to control for analgesic use and other relevant covariates, and failure to report non-significant parameter estimates. This study provides moderate-level evidence for pain catastrophizing as an independent predictor of chronic pain post-TKA. Directions for future research include larger, well-controlled studies with standard pain outcomes, identification of clinically-relevant catastrophizing cut-offs that predict pain outcomes, investigation of other psychosocial risk factors, and assessment of interventions aimed to reduce pain catastrophizing on chronic pain outcomes following TKA surgery.


Mineral trioxide aggregate material use in endodontic treatment: a review of the literature.
The purpose of this paper was to review the composition, properties, biocompatibility, and the clinical results involving the use of mineral trioxide aggregate (MTA) materials in endodontic treatment. Electronic search of scientific papers from January 1990 to August 2006 was accomplished using PubMed and Scopus search engines (search terms: MTA, GMTA, WMTA, mineral AND trioxide AND aggregate). Selected exclusion criteria resulted in 156 citations from the scientific, peer-reviewed dental literature. MTA materials are derived from a Portland cement parent compound and have been demonstrated to be biocompatible endodontic repair materials, with its biocompatible nature strongly suggested by its ability to form hydroxyappatite when exposed to physiologic solutions. With some exceptions, MTA materials provide better microleakage protection than traditional endodontic repair materials using dye, fluid filtration, and bacterial penetration leakage models. In both animal and human studies, MTA materials have been shown to have excellent potential as pulp-capping and pulpotomy medicaments but studies with long-term follow-up are limited. Preliminary studies suggested a favorable MTA material use as apical and furcation restorative materials as well as medicaments for apexogenesis and apexification treatments; however, long-term clinical studies are needed in these areas. MTA materials have been shown to have a biocompatible nature and have excellent potential in endodontic use. MTA materials are a refined Portland cement material and the substitution of Portland cement for MTA products is presently discouraged. Existing human studies involving MTA materials are very promising, however, insufficient randomized, double-blind clinical studies of sufficient duration exist involving MTA for all of its clinical indications. Further clinical studies are needed in these areas.


Reversible changes in pancreatic islet structure and function produced by elevated blood glucose.
Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized.


The Effect of Coconut Oil pulling on Streptococcus mutans Count in Saliva in Comparison with Chlorhexidine Mouthwash.
Oil pulling is an age-old practice that has gained modern popularity in promoting oral and systemic health. The scientific verification for this practice is insufficient. Thus, this study evaluated the effect of coconut oil pulling on the count of Streptococcus mutans in saliva and to compare its efficacy with that of Chlorhexidine mouthwash: in vivo. The null hypothesis was that coconut oil pulling has no effect on the bacterial count in saliva. A randomized controlled study was planned and 60 subjects were selected. The subjects were divided into three groups, Group A: Oil pulling, Group B: Chlorhexidine, and Group C: Distilled water. Group A subjects rinsed mouth with 10 ml of coconut oil for 10 minutes. Group B subjects rinsed mouth with 5 ml Chlorhexidine mouthwash for 1 minute and Group C with 5 ml distilled water for 1 minute in the morning before brushing. Saliva samples were collected and cultured on 1st day and after 2 weeks from all subjects. Colonies were counted to compare the efficacy of coconut oil and Chlorhexidine with distilled water. Statistically significant reduction in S. mutans count was seen in both the coconut oil pulling and Chlorhexidine group. Oil pulling can be explored as a safe and effective alternative to Chlorhexidine. Edible oil-pulling therapy is natural, safe and has no side effects. Hence, it can be considered as a preventive therapy at home to maintain oral hygiene.


Self-reported time spent watching television is associated with arterial stiffness in young adults: the Amsterdam Growth and Health Longitudinal Study.
To investigate whether time spent watching television (a marker of sedentary behaviour) is associated with arterial stiffness, a major determinant of cardiovascular disease, and whether any such association could be explained by related deleterious levels of habitual physical activity (HPA) and/or other lifestyle and biological risk factors. Prospective measures (ages 32 and 36 years) of television time and risk factors were retrieved from 373 participants (196 women) in whom stiffness of the carotid, brachial and femoral arteries was assessed by means of ultrasonography at age 36 years. Data were analysed with generalised estimating equations. Participants with stiffer carotid arteries spent more time (in min/day) watching television during the four preceding years than did those with less stiff arteries, as defined on the basis of the highest compared with the lowest gender-specific tertiles of the distensibility or compliance coefficients (reversed) or the Young's elastic modulus: +22.4 (95%CI 8.7 to 36.1), +18.4 (4.2 to 32.5) and +19.7 (6.0 to 33.4), respectively. These differences were independent of potential confounders, such as vigorous intensity HPA and other lifestyle risk factors, and could only in part (up to 31%) be explained by the adverse associations of television time with traditional biological risk factors. Qualitatively similar results were found for femoral, but not brachial, stiffness estimates. Given the independent associations of time spent watching television and vigorous intensity HPA with arterial stiffness, our study suggests that not only promotion of physical activity, but also discouragement of sedentary behaviours should be targeted in younger adults to prevent arterial stiffening.


Utility of the omentum in the reconstruction of complex extraperitoneal wounds and defects: donor-site complications in 135 patients from 1975 to 2000.
To examine donor-site complications after omental harvest for the reconstruction of extraperitoneal wounds and defects. The omentum, with its immunologic and angiogenic properties, is a versatile organ with well-documented utility in the reconstruction of complex wounds and defects. However, the need for laparotomy and the potential for intraabdominal complications have been cited as relative contraindications to the use of the omentum as a reconstructive flap. Further, few series have assessed long-term results, and no reports have focused on donor-site complications. Patients who underwent reconstruction of extraperitoneal defects with the omentum at a single university healthcare system were identified by searching discharge databases and office records. Charts were reviewed to determine patient demographics, surgical indications and technique, postoperative complications, and outpatient follow-up. Patients with donor-site complications were compared with patients who had no complications using the Student t test and chi-square analysis. Statistical significance was defined at P <.05. From 1975 to 2000, the authors successfully harvested 135 omental flaps (64 pedicled, 71 free transfer) for reconstruction of the following defects: scalp (n = 16), intracranial (n = 1), orbitofacial (n = 33), neck (n = 8), upper extremity (n = 7), lower extremity (n = 4), intrathoracic (n = 3), sternal (n = 34), breast (n = 3), chest wall (n = 18), abdominal wall (n = 1), and perineal (n = 7). Donor-site complications in 25 patients (18.5%) included abdominal wall infection (n = 9), fascial dehiscence (n = 8), symptomatic hernia (n = 8), unplanned reexploration (n = 6), postoperative ileus (n = 3), gastrointestinal hemorrhage (n = 2), delayed splenic rupture (n = 1), gastric outlet obstruction (n = 1), and late partial small bowel obstruction (n = 1). Factors associated with increased donor-site complications included the use of pedicled flaps (compared with free tissue transfer), mediastinitis, advanced age, and pulmonary failure. Of note, 53 patients had undergone previous abdominal surgery; of these, 26 patients required extensive adhesiolysis and 4 patients sustained enterotomies. Eleven patients (8.1%) had partial flap loss and three patients (2.2%) had total flap loss. Mean length of stay was 28 days. Average follow-up was 2.4 years. The death rate was 5.9%. The omentum can be safely harvested and reliably used to reconstruct a diverse range of extraperitoneal wounds and defects. Donor-site complications can be significant but are usually limited to abdominal wall infection and hernia. Risk factors associated with complications include the use of pedicled flaps, mediastinitis, and pulmonary failure. This low rate of donor-site complications strongly supports the use of the omentum in the reconstruction of complex wounds and defects.


Three-dimensional interpenetrating mesoporous carbon confining SnO2 particles for superior sodiation/desodiation properties.
Nanosized SnO2 particles (∼2 nm in diameter) are embedded in ordered mesoporous CMK-8 carbon with unique three-dimensional interconnected pore channels and used as a sodium-ion battery (NIB) anode. Due to the CMK-8 confinement effects, the growth of SnO2 is suppressed during synthesis, leading to high material electroactivity. The CMK-8 not only serves as an electronic conducting pathway, but also creates interpenetrating tunnels, which guarantee electrolyte accessibility and thus Na+ transport throughout the electrode. Moreover, the change in the SnO2 volume during sodiation/desodiation can be accommodated by the CMK-8 framework. With a high tap density of ∼1000 mg cm-3 (vs. ∼800 mg cm-3 for the conventional NIB anode, hard carbon), the SnO2/CMK-8 anode shows a high reversible capacity of 800 mA h g-1 and excellent rate capability, delivering 330 mA h g-1 in ∼10 min. The electrode charge storage mechanism is examined using synchrotron X-ray diffraction. We confirm that CMK-8 incorporation can effectively promote the SnO2-Sn conversion reaction and Sn-Na alloying reaction, which are known to be thermodynamically/kinetically difficult, increasing the electrode charge-discharge performance.


Dynamic elastic behavior of alpha-satellite DNA domains visualized in situ in living human cells.
We have constructed a fluorescent alpha-satellite DNA-binding protein to explore the motile and mechanical properties of human centromeres. A fusion protein consisting of human CENP-B coupled to the green fluorescent protein (GFP) of A. victoria specifically targets to centromeres when expressed in human cells. Morphometric analysis revealed that the alpha-satellite DNA domain bound by CENPB-GFP becomes elongated in mitosis in a microtubule-dependent fashion. Time lapse confocal microscopy in live mitotic cells revealed apparent elastic deformations of the central domain of the centromere that occurred during metaphase chromosome oscillations. These observations demonstrate that the interior region of the centromere behaves as an elastic element that could play a role in the mechanoregulatory mechanisms recently identified at centromeres. Fluorescent labeling of centromeres revealed that they disperse throughout the nucleus in a nearly isometric expansion during chromosome decondensation in telophase and early G1. During interphase, centromeres were primarily stationary, although motility of individual or small groups of centromeres was occasionally observed at very slow rates of 7-10 microns/h.


Bronchial asthma in the Nigerian savanna region. A clinical and laboratory study of 106 patients with a review of the literature on asthma in the tropics.
One hundred and six asthma patients were studied in Zaria in the Nigerian savanna region. This group resembled hospital attenders in general in containing a disproportionately large number of immigrants from southern Nigeria and students undergoing higher education. Childhood asthma was rare. Asthma started after the age of 19 years in 69 per cent of patients. Twenty-seven per cent gave a history of rhinitis but none had had eczema. Twenty-two per cent gave a family history of asthma. Cutaneous hypersensitivity to house dust supported by a history of attacks being precipitated by dust was found in 41 per cent of patients. Asthma was worst in the rainy season in 45 per cent of patients. Mites were found in mattress dust samples; the mean count was 243 mites per g dust; Dermatophagoides farinae formed 86-6 per cent of the total mite population. The variability of airways obstruction averaged 50 per cent of maximum values for forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). The median severity of airways obstruction measured as FEV1/VC per cent was four standard deviations below predicted normal. Eighty-seven per cent of patients were positive to prick skin tests with one or more allergens. The commonest reactions were to house dust (58 per cent), house dust mite (45 per cent) and Dermatophagoides farinae (44 per cent). Fifty-one per cent of a group of controls were also positive on skin testing but the pattern of responses was different from the asthmatic patients. This high proportion of reactors is explained by high allergen load. Serum IgE levels were lower in the asthmatics than in a group of healthy controls who showed the very high levels characteristic of some African populations. We suggest that the controls were protected from atopic disease by developing high blocking levels of non-specific IgE, perhaps in response to gut helminths. The clinical pattern of asthma in Zaria is compared with other countries in the tropical and temperate zones. The particular problems of treating asthma in developing tropical countries are discussed.


New assessment of forearm strength: reliability and validity.
The objective was to determine the reliability of a portable forearm strength hydraulic dynamometer with a doorknob handle and assess its validity compared with a Cybex 6000 (Cybex International, Inc., Medway, MA) isometric torque assessment. Eighteen volunteers (with a total of 30 forearms) participated in this one-session methodological study to determine the intra- and interrater reliability and criterion validity of a forearm dynamometer. Intrarater reliability for both assessors for pronation was (intraclass correlation coefficient [ICC](3,1) = .937-.961) and for supination was (ICC(3,1) = .923-.968). Interrater reliability for pronation was ICC(3,2) = .927 and for supination was ICC(3,2) = .847. Criterion validity of the Baseline hydraulic dynamometer (Fabrication Enterprises Inc., White Plains, NY) compared with the Cybex 6000 was .574-.664 for pronation and .749-.750 for supination. The Baseline hydraulic dynamometer with a more functional doorknob handle had good intra- and interrater reliability and demonstrated moderate validity compared with Cybex 6000 strength testing.


Avenanthramides Prevent Osteoblast and Osteocyte Apoptosis and Induce Osteoclast Apoptosis in Vitro in an Nrf2-Independent Manner.
Oats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin) in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT) and Nrf2 Knockout (KO) osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast apoptosis; further, these regulatory actions are independent of Nrf2.


Phenolic promiscuity in the cell nucleus--epigallocatechingallate (EGCG) and theaflavin-3,3'-digallate from green and black tea bind to model cell nuclear structures including histone proteins, double stranded DNA and telomeric quadruplex DNA.
Flavanols from tea have been reported to accumulate in the cell nucleus in considerable concentrations. The nature of this phenomenon, which could provide novel approaches in understanding the well-known beneficial health effects of tea phenols, is investigated in this contribution. The interaction between epigallocatechin gallate (EGCG) from green tea and a selection of theaflavins from black tea with selected cell nuclear structures such as model histone proteins, double stranded DNA and quadruplex DNA was investigated using mass spectrometry, Circular Dichroism spectroscopy and fluorescent assays. The selected polyphenols were shown to display affinity to all of the selected cell nuclear structures, thereby demonstrating a degree of unexpected molecular promiscuity. Most interestingly theaflavin-digallate was shown to display the highest affinity to quadruplex DNA reported for any naturally occurring molecule reported so far. This finding has immediate implications in rationalising the chemopreventive effect of the tea beverage against cancer and possibly the role of tea phenolics as "life span essentials".


SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.


Synchronous radiation with Er:YAG and Ho:YAG lasers for efficient ablation of hard tissues.
Er:YAG and Ho:YAG laser beams were combined to irradiate hard tissues to achieve highly efficient ablation with low laser power. The delay time between pulses of the two lasers was controlled to irradiate alumina ceramic balls used as hard tissue models. With optimized delay time, the combined laser beam perforated the sample 40% deeper than independent radiation by either an Er:YAG or Ho:YAG laser. An ultra-high-speed camera and an infrared thermography camera were used to observe and investigate the ablation mechanisms.


Fast and cost-effective cyclotron production of 61Cu using a natZn liquid target: an opportunity for radiopharmaceutical production and R&D.
Following our previous work on the production of radiometals, such as 64Cu and 68Ga, through the irradiation of liquid targets using a medical cyclotron, we describe in this paper a technique to produce 61Cu through the irradiation of natural zinc using a liquid target. The proposed method is very cost-effective, as it avoids the use of expensive enriched material, and is fast, as a purified solution of 61CuCl2 is obtained in less than 30 min after the end of beam. Considering its moderate half-life of 3.33 h and favourable decay properties as a positron emitter, 61Cu is a very attractive nuclide for the labelling of PET tracers for pre-clinical and clinical use with PET as well as to support the intense R&D programmes being carried out worldwide by taking advantage of the rich and versatile chemistry of copper.


Revisiting ring-degenerate rearrangements of 1-substituted-4-imino-1,2,3-triazoles.
The 1-substituted-4-imino-1,2,3-triazole motif is an established component of coordination compounds and bioactive molecules, but depending on the substituent identity, it can be inherently unstable due to Dimroth rearrangements. This study examined parameters governing the ring-degenerate rearrangement reactions of 1-substituted-4-imino-1,2,3-triazoles, expanding on trends first observed by L'abbé et al. The efficiency of condensation between 4-formyltriazole and amine reactants as well as the propensity of imine products towards rearrangement was each strongly influenced by the substituent identity. It was observed that unsymmetrical condensation reactions conducted at 70 °C produced up to four imine products via a dynamic equilibrium of condensation, rearrangement and hydrolysis steps. Kinetic studies utilizing 1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carbaldehyde with varying amines showed rearrangement rates sensitive to both steric and electronic factors. Such measurements were facilitated by a high throughput colorimetric assay to directly monitor the generation of a 4-nitroaniline byproduct.


Health care financing policy for hospitalized pulmonary medicine patients.
Several federal bodies provide ongoing analyses of the Medicare DRG prospective hospital payment system. Many states are using DRG prospective "all payor systems" for hospital reimbursement (based on the federal model). In All Payor Systems, Medicare, Medicaid, Blue Cross and other commercial insurers pay by the DRG mode; New York State has been All Payor since 1/1/88. This study simulated DRG All Payor methods on a large sample (n = 1,662) of pulmonary medicine patients for a two-year period using both federal and New York DRG reimbursement now in effect at our hospital. Medicare patients had (on average) a longer hospital length of stay and total hospital cost compared to patients from Medicaid, Blue Cross, and other commercial payors. Medicare patients also had a greater severity of illness compared to patients from Blue Cross Medicaid or other payors. All payors, however, (Medicaid, Blue Cross, Medicare and commercial insurers) generated significant financial risk under the DRG All Payor scheme. These data suggest that federal, state, and private payors may be underreimbursing for the care of the hospitalized pulmonary medicine patients using the DRG prospective hospital payment scheme. Health care financing policy, as demonstrated in this study, may limit both the access and quality of care for many pulmonary medicine patients in the future.


Gaps and challenges to integrating diabetes care in Myanmar.
In common with other low-income countries, diabetes is a growing challenge for Myanmar. Gaps and challenges exist in political commitment, policy development, the health system, treatment-seeking behaviour and the role of traditional medicine. National policies aimed at prevention - such as to promote healthy food, create a healthy environment conducive to increased physical activity, restrict marketing of unhealthy food, and initiate mass awareness-raising programmes - need to be strengthened. Moreover, existing initiatives for prevention of noncommunicable-disease (NCD) are channelled vertically rather than being horizontally integrated. Primary health care is traditionally orientated more towards prevention of infectious diseases and staff often lack training in prevention and control of NCDs. Capacity-building activities have been modest to date, and retaining trained health workers in diabetes-oriented activities is a challenge. The World Health Organization Package of Essential Noncommunicable (PEN) disease interventions for primary health care in low-resource settings has been piloted in Yangon Region and country-wide expansion awaits ministerial approval. Recently, the Myanmar Diabetes Care Model was proposed by the Myanmar Diabetes Association, with the aims of both bridging the gap in diabetes care between rural and urban areas and strengthening care at the secondary and tertiary levels. However, implementation will require policy development for essential drugs and equipment, capacity-strengthening of health-care workers, and an appropriate referral and health-information system.


Sleep in the Social World of College Students: Bridging Interpersonal Stress and Fear of Missing Out with Mental Health.
The college years are characterized by psychosocial and biological phenomena that may impact mental health, such as heightened sensitivity to social stressors and compromises in sleep quantity and quality. The current study uses a biopsychosocial approach to examine the associations among interpersonal stress, Fear of Missing Out (FoMO), insomnia, and mental health. Survey data were collected from 283 undergraduate students (90% female) with a mean age of 21.4 years. A path analysis was utilized to test a mediational model linking interpersonal stress and FoMO with mental health through a mediator of insomnia. We hypothesized that higher levels of interpersonal stress and FoMO would be associated with higher levels of insomnia symptoms, which would in turn be associated with poorer mental health. As predicted, insomnia partially mediated significant associations of interpersonal stress and FoMO with mental health. The association of interpersonal stress with insomnia and mental health was more robust than the association of FoMO with these variables. The pathway from interpersonal stress and/or FoMO, through insomnia, to compromises in mental health may be modifiable through behavioral interventions focusing on coping skills, sleep hygiene, and even technology-related habit changes. Recommendations to help disrupt this pathway, particularly among college students, are discussed.


Selenium accumulation, distribution, and speciation in spineless prickly pear cactus: a drought- and salt-tolerant, selenium-enriched nutraceutical fruit crop for biofortified foods.
The organ-specific accumulation, spatial distribution, and chemical speciation of selenium (Se) were previously unknown for any species of cactus. We investigated Se in Opuntia ficus-indica using inductively coupled plasma mass spectrometry, microfocused x-ray fluorescence elemental and chemical mapping (μXRF), Se K-edge x-ray absorption near-edge structure (XANES) spectroscopy, and liquid chromatography-mass spectrometry (LC-MS). μXRF showed Se concentrated inside small conic, vestigial leaves (cladode tips), the cladode vasculature, and the seed embryos. Se K-edge XANES demonstrated that approximately 96% of total Se in cladode, fruit juice, fruit pulp, and seed is carbon-Se-carbon (C-Se-C). Micro and bulk XANES analysis showed that cladode tips contained both selenate and C-Se-C forms. Inductively coupled plasma mass spectrometry quantification of Se in high-performance liquid chromatography fractions followed by LC-MS structural identification showed selenocystathionine-to-selenomethionine (SeMet) ratios of 75:25, 71:29, and 32:68, respectively in cladode, fruit, and seed. Enzymatic digestions and subsequent analysis confirmed that Se was mainly present in a "free" nonproteinaceous form inside cladode and fruit, while in the seed, Se was incorporated into proteins associated with lipids. μXRF chemical mapping illuminated the specific location of Se reduction and assimilation from selenate accumulated in the cladode tips into the two LC-MS-identified C-Se-C forms before they were transported into the cladode mesophyll. We conclude that Opuntia is a secondary Se-accumulating plant whose fruit and cladode contain mostly free selenocystathionine and SeMet, while seeds contain mainly SeMet in protein. When eaten, the organic Se forms in Opuntia fruit, cladode, and seed may improve health, increase Se mineral nutrition, and help prevent multiple human cancers.


Mixed Streptococcus pneumoniae and Streptococcus pyogenes meningitis in an immunocompromised adult patient: a case report.
Community-acquired meningitis is a monomicrobial infection caused by either viruses or bacteria in the vast majority of patients. We report here one exceptional case of a patient with mixed bacterial meningitis due to Streptococcus pneumoniae and Streptococcus pyogenes. We report the case of a 68-year-old immunocompromised Caucasian man suffering from otitis and then meningitis caused by Streptococcus pneumoniae and Streptococcus pyogenes. Bacteria were undistinguishable by direct microscopic examination of the cerebrospinal fluid. He responded well to treatment with cefotaxime and dexamethasone, with no sequelae observed at the 4-month follow-up. This first reported case of mixed S. pneumoniae and S. pyogenes meningitis illustrates the life-threatening consequences of barotrauma in immunocompromised patients suffering from otorhinolaryngeal infections.


PELP1 oncogenic functions involve alternative splicing via PRMT6.
Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a proto-oncogene that functions as coactivator of the estrogen receptor and is an independent prognostic predictor of shorter survival of breast cancer patients. The dysregulation of PELP1 in breast cancer has been implicated in oncogenesis, metastasis, and therapy resistance. Although several aspects of PELP1 have been studied, a complete list of PELP1 target genes remains unknown, and the molecular mechanisms of PELP1 mediated oncogenesis remain elusive. In this study, we have performed a whole genome analysis to profile the PELP1 transcriptome by RNA-sequencing and identified 318 genes as PELP1 regulated genes. Pathway analysis revealed that PELP1 modulates several pathways including the molecular mechanisms of cancer, estrogen signaling, and breast cancer progression. Interestingly, RNA-seq analysis also revealed that PELP1 regulates the expression of several genes involved in alternative splicing. Accordingly, the PELP1 regulated genome includes several uniquely spliced isoforms. Mechanistic studies show that PELP1 binds RNA with a preference to poly-C, co-localizes with the splicing factor SC35 at nuclear speckles, and participates in alternative splicing. Further, PELP1 interacts with the arginine methyltransferase PRMT6 and modifies PRMT6 functions. Inhibition of PRMT6 reduced PELP1-mediated estrogen receptor activation, cellular proliferation, and colony formation. PELP1 and PRMT6 are co-recruited to estrogen receptor target genes, PELP1 knockdown affects the enrichment of histone H3R2 di-methylation, and PELP1 and PRMT6 coordinate to regulate the alternative splicing of genes involved in cancer. Collectively, our data suggest that PELP1 oncogenic functions involve alternative splicing leading to the activation of unique pathways that support tumor progression and that the PELP1-PRMT6 axis may be a potential target for breast cancer therapy.


Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers.
To determine whether use of topical flea and tick products increases the risk of transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. Case-control study. 87 adult Scottish Terriers with TCC (cases) and 83 adult Scottish Terriers with other health-related conditions (controls). Owners of study dogs were recruited through private veterinary practices and the Scottish Terrier Club of America. History of exposure to flea and tick products 1 year prior to diagnosis of TCC for case dogs and during a comparable period for control dogs was obtained through a questionnaire. Risk of TCC associated with exposure to flea and tick products was determined by means of univariate and multiple logistic regression analysis. After adjustment for host factors, Scottish Terriers treated with topical spot-on flea and tick products containing fipronil or imidacloprid did not have an increased risk of TCC, compared with Scottish Terriers that had never been exposed to any flea and tick products. The risk of TCC associated with use of older topical flea and tick products such as shampoos, dips, powders, sprays, and collars could not be evaluated because of the low number of owners in the study population that had used such products. Results suggest that use of topical spot-on flea and tick products does not increase the risk of TCC in Scottish Terriers.


Use of low-temperature scanning electron microscopy to compare and characterize three classes of snow cover.
This study, which uses low-temperature scanning electron microscopy (LTSEM), systematically sampled and characterized snow crystals that were collected from three unique classes of snow cover: prairie, taiga, and alpine. These classes, which were defined in previous field studies, result from exposure to unique climatic variables relating to wind, precipitation, and air temperature. Snow samples were taken at 10 cm depth intervals from the walls of freshly excavated snow pits. The depth of the snow pits for the prairie, taiga, and alpine covers were 28, 81, and 110 cm, respectively. Visual examination revealed that the prairie snow cover consisted of two distinct layers whereas the taiga and alpine covers had four distinct layers. Visual measurements were able to establish the range of crystal sizes that occurred in each layer, the temperature within the pit, and the snow density. The LTSEM observations revealed the detailed structures of the types of crystals that occurred in the snow covers, and documented the metamorphosis that transpired in the descending layers. Briefly, the top layers from two of the snow covers consisted of freshly fallen snow crystals that could be readily distinguished as plates and columns (prairie) or graupel (taiga). Alternatively, the top layer in the alpine cover consisted of older dendritic crystal fragments that had undergone early metamorphosis, that is, they had lost their sharp edges and had begun to show signs of joining or bonding with neighboring crystals. A unique layer, known as sun crust, was found in the prairie snow cover; however, successive samplings from all three snow covers showed similar stages of metamorphism that led to the formation of depth hoar crystals. These changes included the gradual development of large, three-dimensional crystals having clearly defined flat faces, sharp edges, internal depressions, and facets. The study, which indicates that LTSEM can be used to enhance visual data by systematically characterizing snow crystals that are collected at remote locations, is important for understanding the physics of snowpacks and the metamorphosis that leads to potential avalanche situations. In addition, the metamorphosis of snow crystals must be considered when microwave radiometry is used to estimate the snow water equivalent in the winter snowpack, because large snow crystals more effectively scatter passive microwave radiation than small crystals.


beta-Glucuronidase (GUS) transposons for ecological and genetic studies of rhizobia and other gram-negative bacteria.
A series of transposons are described which contain the gusA gene, encoding beta-glucuronidase (GUS), expressed from a variety of promoters, both regulated and constitutive. The regulated promoters include the tac promoter which can be induced by IPTG, and nifH promoters which are symbiotically activated in legume nodules. One transposon contains gusA with a strong Shine-Dalgarno translation initiation context, but no promoter, and thus acts as a promoter-probe transposon. In addition, a gus operon deletion strain of Escherichia coli, and a transposon designed for use in chromosomal mapping using PFGE, are described. The GUS transposons are constructed in a mini-Tn5 system which can be transferred to Gram-negative bacteria by conjugation, and will form stable genomic insertions. Due to the absence of GUS activity in plants and many bacteria of economic importance, these transposons constitute powerful new tools for studying the ecology and population biology of bacteria in the environment and in association with plants, as well as for studies of the fundamental molecular basis of such interactions. The variety of assays available for GUS enable both quantitative assays and spatial localization of marked bacteria to be carried out.


Greater parallel heterogeneity of airway narrowing and airway closure in asthma measured by high-resolution CT.
Heterogeneous airway narrowing and closure are characteristics of asthma. However, they have never been quantified by direct measurements of parallel sister airways obtained from image data, and the anatomical basis of these processes remains unknown. Seven normal and nine asthmatic subjects underwent high-resolution CT, before and after methacholine challenge. Mean lumen areas of the entire airways were measured in 28 and 24 parallel sister airway pairs (a pair of airways arising from the same bifurcation) respectively (range 1.0-8.7 mm diameter). Heterogeneous narrowing was defined as the median difference in percentage narrowing between parallel sister airways. Forced oscillatory respiratory resistance (Rrs) and spirometry were measured before and after methacholine challenge conducted while supine. The airways of asthmatics were smaller at baseline, and following bronchoconstriction there were similar decreases in FEV1, increases in Rrs and mean narrowing of airways for asthmatic and non-asthmatic groups. Non-asthmatics required higher doses of methacholine than asthmatics to achieve the same changes. However, parallel heterogeneity (median (IQR) 33% (27-53%) vs 11% (9-18%), p<0.001) and airway closure (24.1% and 7.7%, p=0.001, χ(2)) were greater in asthmatics versus non-asthmatics. We found clear evidence of differences in airway behaviour in the asthmatic group. Asthmatic airways were narrower at baseline and responded to inhaled methacholine by more heterogeneous narrowing of parallel sister airways and greater airway closure.


Small business needs assessment: a comparison of dental educators' responses with SBDC survey results.
A primary focus of dental education is to teach students the knowledge, skills, and values essential for practicing dentistry. However, the preparation of dentists to manage a business is frequently cited as inadequate. A survey was prepared to assess teachers' opinions of business instructional topics: challenges; desired training; employee benefits; learning resources; importance of business topics; and appropriateness of time allocations. The purpose of this project is to compare opinions of teachers of dental practice management with key management aspects reported for service businesses by the Small Business Development Center (SBDC). Practice management teachers from forty-eight (89 percent) schools responded to the survey. They indicated that several challenges confronting dentists are similar to other service businesses. Dentists, however, rank customer relations appreciably higher. In order of importance of teaching topics, the practice management teachers rank ethics and personnel management as a high priority and planning as a low priority. Awareness of the similarities and differences in the perceptions of practice management teachers and businesspeople may result in instructional improvements.


Computerized neurocognitive testing for the management of sport-related concussions.
To describe the prevalence of computerized neurocognitive testing for the assessment of high school athletes who sustain concussions, and to describe associations between using computerized neurocognitive tests, timing of return-to-play, and medical provider managing the athlete. Concussions recorded in the High School Reporting Information Online injury surveillance system during the 2009-2010 academic year were included. Measures of association between use of computerized neurocognitive testing and outcomes were analyzed. A questionnaire was sent to athletic trainers (ATs) querying the use of computerized neurocognitive testing. χ(2) analyses were conducted for categorical variables. Logistic regression analyses were used to adjust for potential confounders. Statistical significance was set at P < .05. High School Reporting Information Online recorded 1056 concussions. Athletes who underwent computerized neurocognitive testing were less likely to be returned to play within 10 days of injury (38.5% vs 55.7%, P < .001) and more likely to be returned to play by a physician (60.9% vs 45.6%, P < .001). We had a response rate of 97.3% for the survey. Of respondents, 39.9% used computerized neurocognitive testing; 93.0% of those used ImPACT. Tests were most often interpreted by ATs (78.9%) and/or physicians (78.8%), as opposed to neuropsychologists (16.9%). Approximately 40% of US high schools that employ an AT use computerized neurocognitive tests when managing sport-related concussions. Tests are most often interpreted by ATs and physicians, as opposed to neuropsychologists. Computerized neurocognitive tests are significantly associated with the timing of return-to-play.


Responses of human cells to ZnO nanoparticles: a gene transcription study.
The gene transcript profile responses to metal oxide nanoparticles was studied using human cell lines derived from the colon and skin tumors. Much of the research on nanoparticle toxicology has focused on models of inhalation and intact skin exposure, and effects of ingestion exposure and application to diseased skin are relatively unknown. Powders of nominally nanosized SiO2, TiO2, ZnO and Fe2O3 were chosen because these substances are widely used in consumer products. The four oxides were evaluated using colon-derived cell lines, RKO and CaCo-2, and ZnO and TiO2 were evaluated further using skin-derived cell lines HaCaT and SK Mel-28. ZnO induced the most notable gene transcription changes, even though this material was applied at the lowest concentration. Nano-sized and conventional ZnO induced similar responses suggesting common mechanisms of action. The results showed neither a non-specific response pattern common to all substances nor synergy of the particles with TNF-α cotreatment. The response to ZnO was not consistent with a pronounced proinflammatory signature, but involved changes in metal metabolism, chaperonin proteins, and protein folding genes. This response was observed in all cell lines when ZnO was in contact with the human cells. When the cells were exposed to soluble Zn, the genes involved in metal metabolism were induced but the genes involved in protein refoldling were unaffected. This provides some of the first data on the effects of commercial metal oxide nanoparticles on human colon-derived and skin-derived cells.


Factors influencing intraocular pressure in cultured human anterior segments.
To determine why variations in intraocular pressure (IOP) occur in cultured human anterior segments despite a constant rate of infusion of culture medium. Two types of variations occur: an initial elevation of IOP and small changes in baseline IOP. Anterior segments from human eyes were placed in perfusion organ culture. In cultures with initially high IOP, eyes were fixed at the high IOP level and histologic examination performed. In other cultures with high initial IOP, effluent medium was collected and subsequently reinfused after IOP had decreased to baseline. In cultures with stable baseline IOP, cell fragments from monolayer-cultured cells, or human genomic DNA, were infused at concentrations equivalent to 30,000 to 300,000 cells. Electron microscopy of initially high-pressure cultures revealed scattered cell debris throughout the meshwork in greater amounts than found in eyes without initially high IOP. Reinfusion of effluent media from cultures with high initial pressures caused elevation of IOP. Centrifugation of effluent media lessened this elevation of IOP. In cultures with stable baseline IOP, infusion of cell fragments or genomic DNA raised IOP in a dose-dependent manner, with elevation of IOP for a minimum of 24 hours. Cell debris can elevate IOP during the initial culture period, and after baseline pressures are established. Cell fragments and DNA increase IOP in a dose-dependent manner. The variations in baseline IOP seen during culture are probably caused by cell fragments and debris from dying cells in the meshwork, ciliary body, and other anterior segment tissues.


Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency.
Prospective observation in a neonate with guanidinoacetate methyltransferase deficiency (GAMT-D), a severe neurometabolic disorder, revealed increased guanidinoacetate levels at birth. After 14-month treatment with creatine, high-dose ornithine, benzoate, and an arginine-restricted diet, the patient's development is normal and she does not present any symptoms of GAMT-D. The authors' observation indicates that early detection of GAMT-D is possible in the neonatal period, and presymptomatic treatment may prevent its manifestation.


Tremor in a population-based cohort of children in New York City.
There have been virtually no surveys of the prevalence, clinical features, or correlates of tremor in children and none in the United States. A total of 317 children (age 11.0 ± 1.1 years; range, 9.0 to 14.7) underwent an evaluation at one time point. Each drew Archimedes spirals, which were rated by a senior neurologist specializing in movement disorders. A spiral score of 1 (mild but consistent tremor) was present in either hand in 105 (33.1%) children; a higher score (1.5, mild-to-moderate tremor) was present in either hand in 7 (2.2%) children. Higher spiral scores were associated with poorer motor hand function as assessed using the Purdue Pegboard test. Spiral scores were higher in boys than girls, were inversely associated with age, and were higher in the nondominant than dominant hand. Spiral scores were highest in children who were taking psychiatric medications and in children with psychiatric or neurological disorders. Mild tremor is common in children and covaries significantly with several demographic and clinical factors as well as usage of certain medications. It also lessens with advancing age. Rather than an isolated finding, tremor was associated with other measures of poorer motor hand function.


Cellular-telephone use and brain tumors.
Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.


Formation of phase separated vesicles by double layer cDICE.
Recently, continuous droplet interface crossing encapsulation (cDICE) was developed, which allows fast and efficient production of giant unilamellar vesicles (GUVs) under high salt conditions, at low temperature and with low consumption of the encapsulated proteins. Unfortunately, cholesterol encapsulation within the lipid bilayer was not efficient for the cDICE protocol so far and thus the formation of phase separated vesicles was limited. Here we present a modified version of cDICE that allows incorporation of cholesterol into lipid bilayers and enables the reproducible formation of phase-separated vesicles. We show that cholesterol incorporation relies on the amount of mineral oil in the lipid-oil emulsions, which is essential for protein encapsulation inside GUVs by cDICE. The possibility of creating phase separated vesicles by cDICE will enable the study of the interdependence between phase separation and cytoskeletal proteins under confinement.


Complexing Methylene Blue with Phosphorus Dendrimers to Increase Photodynamic Activity.
The efficiency of photodynamic therapy is limited mainly due to low selectivity, unfavorable biodistribution of photosensitizers, and long-lasting skin sensitivity to light. However, drug delivery systems based on nanoparticles may overcome the limitations mentioned above. Among others, dendrimers are particularly attractive as carriers, because of their globular architecture and high loading capacity. The goal of the study was to check whether an anionic phosphorus dendrimer is suitable as a carrier of a photosensitizer-methylene blue (MB). As a biological model, basal cell carcinoma cell lines were used. We checked the influence of the MB complexation on its singlet oxygen production ability using a commercial fluorescence probe. Next, cellular uptake, phototoxicity, reactive oxygen species (ROS) generation, and cell death were investigated. The MB-anionic dendrimer complex (MB-1an) was found to generate less singlet oxygen; however, the complex showed higher cellular uptake and phototoxicity against basal cell carcinoma cell lines, which was accompanied with enhanced ROS production. Owing to the obtained results, we conclude that the photodynamic activity of MB complexed with an anionic dendrimer is higher than free MB against basal cell carcinoma cell lines.


Assessing bone thickness in the infrazygomatic crest area aiming the orthodontic miniplates positioning: a tomographic study.
Due to the increasing use of miniplates for anchorage purposes in orthodontics, it is very important to know more about infrazigomatic crest anatomy (thickness), in adult patients. Evaluate the infrazygomatic crest region thickness, in adult (male and female) patients. Cone-beam computerized tomography (CBCT) images from 40 patients were used to assess cross-sectional measurements of the infrazygomatic crest region. Measurement 1 considered thickness 2 mm above the distobuccal root of the permanent maxillary first molar, while measurement 2 was taken 2 mm above the first measurement. The mean thickness of the infrazygomatic crest in males was 3.55 mm for measurement 1 and 2.84 mm for measurement 2, while in females these were 2.37 mm and 2.24 mm, respectively. The authors concluded that the overall mean thickness of the infrazygomatic crest was 2.49 mm with respect to measurement 1, and 2.29 mm for measurement 2, with no statistically significant differences between gender.


Arabidopsis TH2 Encodes the Orphan Enzyme Thiamin Monophosphate Phosphatase.
To synthesize the cofactor thiamin diphosphate (ThDP), plants must first hydrolyze thiamin monophosphate (ThMP) to thiamin, but dedicated enzymes for this hydrolysis step were unknown and widely doubted to exist. The classical thiamin-requiring th2-1 mutation in Arabidopsis thaliana was shown to reduce ThDP levels by half and to increase ThMP levels 5-fold, implying that the THIAMIN REQUIRING2 (TH2) gene product could be a dedicated ThMP phosphatase. Genomic and transcriptomic data indicated that TH2 corresponds to At5g32470, encoding a HAD (haloacid dehalogenase) family phosphatase fused to a TenA (thiamin salvage) family protein. Like the th2-1 mutant, an insertional mutant of At5g32470 accumulated ThMP, and the thiamin requirement of the th2-1 mutant was complemented by wild-type At5g32470 Complementation tests in Escherichia coli and enzyme assays with recombinant proteins confirmed that At5g32470 and its maize (Zea mays) orthologs GRMZM2G148896 and GRMZM2G078283 are ThMP-selective phosphatases whose activity resides in the HAD domain and that the At5g32470 TenA domain has the expected thiamin salvage activity. In vitro and in vivo experiments showed that alternative translation start sites direct the At5g32470 protein to the cytosol and potentially also to mitochondria. Our findings establish that plants have a dedicated ThMP phosphatase and indicate that modest (50%) ThDP depletion can produce severe deficiency symptoms.


Extremity War Injuries VIII: sequelae of combat injuries.
The 2013 Extremity War Injury symposium focused on the sequelae of combat-related injuries, including posttraumatic osteoarthritis, amputations, and infections. Much remains to be learned about posttraumatic arthritis, and there are few circumstances in which a definitive arthroplasty should be performed in an acutely injured and open joint. Although the last decade has seen tremendous advances in the treatment of combat upper extremity injuries, many questions remain unanswered, and continued research focusing on improving reconstruction of large segmental defects remains critical. Discussion of infection centered on the need for novel methods to reduce the bacterial load following the initial débridement procedures. Novel methods of delivering antimicrobial therapy and anti-inflammatory medications directly to the wound were discussed as well as the need for near real-time assessment of bacterial and fungal burden and further means of prevention and treatment of biofilm formation and the importance of animal models to test therapies discussed. Moderators and lecturers of focus groups noted the continuing need for improved prehospital care in the management of junctional injuries, identified optimal strategies for both surgical repair and/or reconstruction of the ligaments in multiligamentous injuries, and noted the need to mitigate bone mineral density loss following amputation and/or limb salvage as well as the necessity of developing better methods of anticipating and managing heterotopic ossification.


Characterization of the displacement response in chromatic confocal microscopy with a hybrid radial basis function network.
Characterization of the displacement response is critical for accurate chromatic confocal measurement. Current characterization methods usually provide a linear or polynomial relationship between the extracted peak wavelengths of the spectral signal and displacement. However, these methods are susceptible to errors in the peak extraction algorithms and errors in the selected model. In this paper, we propose a hybrid radial basis function network method to characterise the displacement response. With this method, the peak wavelength of the spectral signal is firstly extracted with a state-of-art peak extraction algorithm, following which, a higher-accuracy chromatic dispersion model is applied to determine the displacement-wavelength relationship. Lastly, a radial basis function network is optimized to provide a mapping between the spectral signals and the residual fitting errors of the chromatic dispersion model. Using experimental tests, we show that the hybrid radial basis function network method significantly improves the measurement accuracy, when compared to the existing characterizing methods.


Technique of Arthroscopically Assisted Transtrochanteric Drilling for Femoral Head Chondral Defects.
Microfracture is a marrow-stimulation technique in which damaged cartilage is drilled or punched, perforating the subchondral bone and generating a blood clot within the defect that matures into fibrocartilage. Microfracture for the treatment of small cartilage defects of the hip has shown good results. Arthroscopic procedures are less invasive than open procedures and have a reduced incidence of complications such as infection or avascular necrosis of the femoral head. Furthermore, arthroscopic procedures allow for a shorter recovery time, resulting in not only lower overall treatment costs but also higher patient satisfaction. Medial and parafoveal cartilage defects of the femoral head can be challenging to effectively microfracture using standard arthroscopy portals because of the acute angles required for instrument manipulation. This report describes a technique for microfracturing these challenging areas of the femoral head using a 2.7-mm K-wire and drilling in a transtrochanteric direction using arthroscopic and imaging guidance to target the area of chondral damage.


Prevalence and Diversity among Anaplasma phagocytophilum Strains Originating from Ixodes ricinus Ticks from Northwest Norway.
The tick-borne pathogen Anaplasma phagocytophilum causes great concern for livestock farmers. Tick-borne fever is a widespread disease in Norway, and antibodies have been produced amongst sheep, roe deer, red deer, and moose. The main vector Ixodes ricinus is found along the Norwegian coastline as far north as the Arctic Circle. A total number of 1804 I. ricinus ticks were collected and the prevalence of the pathogen was determined by species-specific qPCR. The overall infection rate varied from 2.83% to 3.32%, but there were no significant differences (p = 0.01) in the overall infection rate in 2010, 2011, or 2012. A multilocus sequencing analysis was performed to further characterise the isolates. The genotyping of 27 strains resulted in classification into 19 different sequences types (ST), none of which was found in the MLST database. The nucleotide diversity was for every locus <0.01, and the number of SNPs was between 1 and 2.8 per 100 bp. The majority of SNPs were synonymous. A goeBURST analysis demonstrated that the strains from northwest Norway cluster together with other Norwegian strains in the MLST database and the strains that are included in this study constitute clonal complexes (CC) 9, 10, and 11 in addition to the singleton.


How do individuals with autism plan their movements?
Two experiments investigated how persons with and without autism plan manual aiming movements when advance information is direct and when strategic planning is required. In Experiment 1 advance information about hand, direction, and/or movement amplitude was manipulated. Reaction times suggested both groups adopted a hierarchical pattern of movement planning. In Experiment 2, participants performed aiming movements to one of two targets that were the same or different size. Participants without autism varied the starting location in anticipation of specific target stimuli whereas participants with autism consistently selected the midpoint. Overall, individuals with autism used advance information to plan their movements when this information was direct. However, their performance became stereotyped when strategies were self-generated.


Evaluation of SNP Genotyping in Alpacas Using the Bovine HD Genotyping Beadchip.
Alpacas are one of four South American Camelid species living in the highlands of the Andes. Production of alpaca fiber contributes to the economy of the region and the livelihood of many rural families. Fiber quantity and quality are important and in need of a modern breeding program based on genomic selection to accelerate genetic gain. To achieve this is necessary to discover enough molecular markers, single nucleotide polymorphisms (SNPs) in particular, to provide genome coverage and facilitate genome wide association studies to fiber production characteristics. The aim of this study was to discover alpaca SNPs by genotyping forty alpaca DNA samples using the BovineHD Genotyping Beadchip. Data analysis was performed with GenomeStudio (Illumina) software. Because different filters and thresholds are reported in the literature we investigated the effects of no-call threshold (≥0.05, ≥0.15, and ≥0.25) and call frequency (≥0.9 and =1.0) in identifying positive SNPs. Average GC Scores, calculated as the average of the 10% and 50% GenCall scores for each SNP (≥0.70) and the GenTrain score ≥ 0.25 parameters were applied to all comparisons. SNPs with minor allele frequency (MAF) ≥ 0.05 or ≥ 0.01 were retained. Since detection of SNPs is based on the stable binding of oligonucleotide probes to the target DNA immediately adjacent to the variant nucleotide, all positive SNP flanking sequences showing perfect alignments between the bovine and alpaca genomes for the first 21 or 26 nucleotides flanking the variant nucleotide at either side were selected. Only SNPs localized in one scaffold were assumed unique. Unique SNPs identified in both reference genomes were kept and mapped on the Vicugna_pacos 2.0.2 genome. The effects of the no-call threshold ≥ 0.25, call frequency = 1 and average GC ≥ 0.7 were meaningful and identified 6756 SNPs of which 400 were unique and polymorphic (MAF ≥ 0.01). Assignment to alpaca chromosomes was possible for 292 SNPs. Likewise, 209 SNPs were localized in 202 alpaca gene loci and 29 of these share the same loci with the dromedary. Interestingly, 69 of 400 alpaca SNPs have 100% similarity with dromedary.


Spatial patterns of alkaline phosphatase expression within bacterial colonies and biofilms in response to phosphate starvation.
The expression of alkaline phosphatase in response to phosphate starvation was shown to be spatially and temporally heterogeneous in bacterial biofilms and colonies. A commercial alkaline phosphatase substrate that generates a fluorescent, insoluble product was used in conjunction with frozen sectioning techniques to visualize spatial patterns of enzyme expression in both Klebsiella pneumoniae and Pseudomonas aeruginosa biofilms. Some of the expression patterns observed revealed alkaline phosphatase activity at the boundary of the biofilm opposite the place where the staining substrate was delivered, indicating that the enzyme substrate penetrated the biofilm fully. Alkaline phosphatase accumulated linearly with time in K. pneumoniae colonies transferred from high-phosphate medium to low-phosphate medium up to specific activities of 50 mumol per min per mg of protein after 24 h. In K. pneumoniae biofilms and colonies, alkaline phosphatase was initially expressed in the region of the biofilm immediately adjacent to the carbon and energy source (glucose). In time, the region of alkaline phosphatase expression expanded inward until it spanned most, but not all, of the biofilm or colony depth. In contrast, expression of alkaline phosphatase in P. aeruginosa biofilms occurred in a thin, sharply delineated band at the biofilm-bulk fluid interface. In this case, the band of activity never occupied more than approximately one-sixth of the biofilm. These results are consistent with the working hypothesis that alkaline phosphatase expression patterns are primarily controlled by the local availability of either the carbon and energy source or the electron acceptor.


Antcin B and its ester derivative from Antrodia camphorata induce apoptosis in hepatocellular carcinoma cells involves enhancing oxidative stress coincident with activation of intrinsic and extrinsic apoptotic pathway.
The triterpenoids methylantcinate B (MAB) and antcin B (AB), isolated from the medicinal mushroom Antrodia camphorata , have been identified as strong cytotoxic agents against various type of cancer cells; however, the mechanisms of MAB- and AB-induced cytotoxicity have not been adequately explored. This study investigated the roles of caspase cascades, reactive oxygen species (ROS), DNA damage, mitochondrial disruption, and Bax and Bcl-2 proteins in MAB- and AB-induced apoptosis of hepatocellular carcinoma (HCC) HepG2 cells. Here, we showed that MAB and AB induced apoptosis in HepG2 cells, as characterized by increased DNA fragmentation, cleavage of PARP, sub-G1 population, chromatin condensation, loss of mitochondrial membrane potential, and release of cytochrome c. Increasing the levels of caspase-2, -3, -8, and -9 activities was involved in MAB- and AB-induced apoptosis, and they could be attenuated by inhibitors of specific caspases, indicating that MAB and AB triggered the caspase-dependent apoptotic pathway. Additionally, the enhanced apoptotic effect correlates with high expression of Fas, Fas ligand, as well as Bax and decreased protein levels of Bcl-(XL) and Bcl-2, suggesting that both the extrinsic and intrinsic apoptosis pathways were involved in the apoptotic processes. Incubation of HepG2 cells with antioxidant enzymes superoxide dismutase and catalase and antioxidants N-acetylcysteine and ascorbic acid attenuated the ROS generation and apoptosis induced by MAB and AB, which indicate that ROS plays a pivotal role in cell death. NADPH oxidase activation was observed in MAB- and AB-stimulated HepG2 cells; however, inhibition of such activation by diphenylamine significantly blocked MAB- and AB-induced ROS production and increased cell viability. Taken together, our results provide the first evidence that triterpenoids MAB and AB induced a NADPH oxidase-provoked oxidative stress and extrinsic and intrinsic apoptosis as a critical mechanism of cause cell death in HCC cells.


Surveillance at Private Laboratories Identifies Small Outbreaks of Hepatitis E in Urban Bangladesh.
Although large outbreaks of hepatitis E are regularly identified in south Asia, the majority of south Asian countries lack surveillance systems for this disease, which has hindered burden of disease estimates and prioritization of resources for prevention. Our study aimed to identify small hepatitis E outbreaks through a sentinel private laboratory in Dhaka, Bangladesh. We identified patients with detectable IgM antibody against hepatitis E virus. We defined a small outbreak as at least two laboratory-confirmed cases or ≥ 2 acute jaundice cases from the sentinel cases' family, neighborhood, or workplace. From November 2008 to November 2009, we identified 29 small outbreaks of hepatitis E from one private laboratory. The median number of cases in each outbreak was three. Cases were identified every month. Eighteen outbreaks occurred among families or neighbors, and 11 in the workplace. Among 103 cases identified as part of outbreaks, 31 (30%) sought care for diagnosis. In Bangladesh, collaboration between government public health surveillance and private laboratories can strengthen capacity for outbreak detection and improve estimates of disease burden.


Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey.
There are a number of different approaches to the initial treatment of juvenile dermatomyositis (JDM). We assessed the therapeutic approaches of North American pediatric rheumatologists to inform future studies of therapy in JDM. A survey describing clinical cases of JDM was sent to pediatric rheumatologists. The cases described children with varying severity of typical disease, disease with atypical features, or refractory disease. Three open-ended questions were asked following each case: (1) What additional investigations would you order; (2) What medicine(s) would you start (dose, route, frequency, adjustment over time); and (3) What nonmedication treatment(s) would you start. The response rate was 84% (141/167). For typical cases of JDM, regardless of severity, almost all respondents used corticosteroids and another medication, methotrexate (MTX) being the most commonly used. The route and pattern of corticosteroid administration was variable. Intravenous immunoglobulin (IVIG) was used more frequently for more severe disease, for refractory disease, and for prominent cutaneous disease. Hydroxychloroquine was often used in milder cases and cases principally characterized by rash. Cyclophosphamide was reserved for ulcerative disease and JDM complicated by lung disease. For the majority of North American pediatric rheumatologists, corticosteroids and MTX appear to be the standard of care for typical cases of JDM. There is variability, however, in the route of administration of corticosteroids and use of IVIG and hydroxychloroquine.


New drugs targeting Th2 lymphocytes in asthma.
Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic phenotypes. Some of these new Th2-oriented strategies may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease.


For real! XCS with continuous-valued inputs.
Many real-world problems are not conveniently expressed using the ternary representation typically used by Learning Classifier Systems and for such problems an interval-based representation is preferable. We analyse two interval-based representations recently proposed for XCS, together with their associated operators and find evidence of considerable representational and operator bias. We propose a new interval-based representation that is more straightforward than the previous ones and analyse its bias. The representations presented and their analysis are also applicable to other Learning Classifier System architectures. We discuss limitations of the real multiplexer problem, a benchmark problem used for Learning Classifier Systems that have a continuous-valued representation, and propose a new test problem, the checkerboard problem, that matches many classes of real-world problem more closely than the real multiplexer. Representations and operators are compared using both the real multiplexer and checkerboard problems and we find that representational, operator and sampling bias all affect the performance of XCS in continuous-valued environments.


Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer's Disease Brains.
Alzheimer's disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood-brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.


Safety and comfort during sedation for diagnostic or therapeutic procedures.
Sedation during diagnostic or therapeutic procedures must be safe and comfortable for patients. To achieve this, additional suitably qualified staff must be available throughout the procedure to administer sedation and monitor the patient. Anaesthesiologists possess the necessary knowledge and skills to perform sedation safely but are often unavailable. Non-anaesthesiologists performing sedation should be fully trained in the physiology of sedation, the pharmacology of sedatives and analgesics, the monitoring of patients, and in airway support, ventilatory care, and cardiopulmonary resuscitation. The presence of an anaesthesiologist is desirable when dealing with patients at high-risk of complications. Good sedation practice involves presedation assessment and optimal selection of patients, careful monitoring and support from dedicated staff, and adherence to recovery and discharge criteria.


Revisited: Comparison of Empirical Methods to Evaluate Visualizations Supporting Crafting and Assembly Purposes.
Ubiquitous, situated, and physical visualizations create entirely new possibilities for tasks contextualized in the real world, such as doctors inserting needles. During the development of situated visualizations, evaluating visualizations is a core requirement. However, performing such evaluations is intrinsically hard as the real scenarios are safety-critical or expensive to test. To overcome these issues, researchers and practitioners adapt classical approaches from ubiquitous computing and use surrogate empirical methods such as Augmented Reality (AR), Virtual Reality (VR) prototypes, or merely online demonstrations. This approach's primary assumption is that meaningful insights can also be gained from different, usually cheaper and less cumbersome empirical methods. Nevertheless, recent efforts in the Human-Computer Interaction (HCI) community have found evidence against this assumption, which would impede the use of surrogate empirical methods. Currently, these insights rely on a single investigation of four interactive objects. The goal of this work is to investigate if these prior findings also hold for situated visualizations. Therefore, we first created a scenario where situated visualizations support users in do-it-yourself (DIY) tasks such as crafting and assembly. We then set up five empirical study methods to evaluate the four tasks using an online survey, as well as VR, AR, laboratory, and in-situ studies. Using this study design, we conducted a new study with 60 participants. Our results show that the situated visualizations we investigated in this study are not prone to the same dependency on the empirical method, as found in previous work. Our study provides the first evidence that analyzing situated visualizations through different empirical (surrogate) methods might lead to comparable results.


A case series of sotalol-induced torsade de pointes in patients with atrial fibrillation--a tale with a twist.
Sotalol is a potent antiarrhythmic often used in patients with atrial fibrillation. However, it has been associated with a risk of provoking other potentially dangerous arrhythmias, especially if used in high doses and in patients with uncorrected electrolyte imbalance or impaired renal and cardiac function. We present 4 patients with atrial fibrillation treated with sotalol who developed torsade de pointes due to marked prolongation of the QT interval. While 1 patient had renal failure, all had normal left ventricular function. One patient had been treated with sotalol for more than 10 months before developing torsade de pointes precipitated by hypokalaemia, while another had tolerated sotalol for a 3-month period before the drug was discontinued, and only developed torsade de pointes when the drug was restarted 2 years later. Significantly, the doses used in all patients were relatively low, in contrast to most other reported cases where higher doses were used. As with all antiarrhythmic therapy, these cases illustrate the need for close follow-up of patients treated with sotalol, even if relatively low doses are used. In addition, patients who had previously tolerated the drug well are still susceptible to its proarrhythmic effects.


Studies on cell-cycle synchronization in the asexual erythrocytic stages of Plasmodium falciparum.
Multiplication of Plasmodium parasites within human erythrocytes is essential to malarial disease. The cell-division cycle of this organism, however, is still poorly understood. In other eukaryotes, various techniques for (apparent) cell-cycle synchronization have been used to shed light on the mechanisms involved in cell division and its control. Thus far there is no technique for cell-cycle synchronization (as opposed to selection of parasites of a limited age-range) in Plasmodium. We therefore investigated the possibility that inhibitors of DNA synthesis, the mitotic spindle, or cell-cycle control elements (such as cyclin-dependent kinases) could be used to synchronize P. falciparum cultures to a particular cell-cycle phase. Surprisingly, most of these compounds did not cause a block at a specific phase. Three compounds, Hoechst 33342, roscovitine and L-mimosine, did block development at the trophozoite-schizont transition (S or G2 phase). The block caused by the latter 2 inhibitors was reversible, suggesting that they might be used as synchronizing agents. However, a consideration of the perturbing effects of inhibitors and problems with 'batch' synchronization techniques in general lead us to believe that any results obtained using roscovitine- or L-mimosine-treated parasites may not be reflective of the normal cell cycle.